Pneumonic plague, caused by the same organism responsible for bubonic plague, is the deadliest manifestation of disease caused by the bacterium Yersinia pestis. Although the current worldwide incidence of plague is low by historical standards, the possible combination of widespread aerosol dissemination and rapid disease progression are of particular concern for defense against bioterrorism with Y. pestis. To initiate mammalian infection, Y. pestis employs a number of mechanisms to interfere with host inflammatory responses, and yet the later stages of pneumonic plague are marked by dramatic inflammation. Thus, Y. pestis must control and subsequently adapt to at least two distinct phases of infection (anti-inflammatory and pro-inflammatory) in order to be a successful pathogen of the respiratory system. This proposal will: (a) explore the ability of Y. pestis to modulate the host response during the anti- and pro-inflammatory phases of primary pneumonic plague via the targeted deletion of bacterial immunomodulatory genes, and (b) identify and study the early and late transcriptional responses by Y. pestis during pneumonic plague using in vivo DNA microarray technology. [unreadable] [unreadable] [unreadable]